Background and Purposes: Through this study, we hope to gain more insights into the differences in outcome following an ischemic stroke between the floating population and the indigenous population of Shanghai.Method: In this retrospective cohort study, we analyzed patients with first-ever acute ischemic stroke who were admitted to a comprehensive stroke center in the Minhang district, Shanghai, from January 1, 2019, to December 31, 2020. All patient's demographic data and medical histories were prospectively collected and they were followed up for at least 3 months. The Indigenous population of Shanghai was defined as patients with an identification number starting with 310. All others were treated as floating population. The primary outcome was defined as an unfavorable prognosis at 3 months, with a modified Rankin Scale (mRS) score above 1. Secondary outcomes included the use of emergency medical service (EMS), 3 h arrival rate, and endovascular therapy in eligible patients. Logistic regression analysis was applied to investigate the differences.Results: Finally, 698 patients with first-ever acute ischemic stroke were included (with mean age of 65.32 years, 74.6% men). Of these, 302 patients belonged to the floating population group. Indigenous populations with ischemic stroke were older than the floating population (68.26 years vs. 61.47 years, P < 0.001). The floating population was more likely to achieve favorable outcomes at 3 months compared with the indigenous population in multivariable logistic regression analysis [Odds ratio (OR): 0.49, 95% CI: 0.32–0.75, P = 0.001]. The use of EMS, 3 h arrival rate, and the application of endovascular therapy were comparable between the floating population and indigenous population (OR: 0.89, 95% CI: 0.62–1.27, P = 0.519; OR: 0.78, 95% CI: 0.56–1.09, P = 0.14; and OR: 0.82, 95% CI: 0.54–1.26, P = 0.365, respectively).Conclusion: Compared with the indigenous population, the floating population with the first-ever ischemic stroke was more likely to have a favorable outcome at 3 months.